Anaplastic glioma

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Seema Nagpal, MD
Palo Alto, CA

If you are looking for other subtypes of brain cancer, please go to the CNS cancers category page.

18 regimens on this page
37 variants on this page

Contents


Guidelines

EANO

ESMO

NCCN

Adjuvant therapy

Carmustine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Chang et al 1983 Phase III (E) RT alone Seems not superior
Levin et al. 1985 (NCOG 6G61) Phase III (C) PCV Seems to have inferior OS (*)

Note: Chang et al. 1983 was technically a negative study, although the subgroup of patients aged 40 to 60 had superior survival in this arm. Efficacy for NCOG 6G61 is based on the 1990 update.

Preceding treatment

  • Chang et al. 1983: Surgery, then RT
  • NCOG 6G61: Surgery, then Hydrea & WBRT

Chemotherapy

References

  1. Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukada Y. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: a joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983 Sep 15;52(6):997-1007. link to original article PubMed
  2. NCOG 6G61: Levin VA, Wara WM, Davis RL, Vestnys P, Resser KJ, Yatsko K, Nutik S, Gutin PH, Wilson CB. Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. J Neurosurg. 1985 Aug;63(2):218-23. link to original article contains verified protocol PubMed
    1. Update: Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2):321-4. link to original article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Thomas et al. 2001 (MRC BR05) Phase III (C) PCV Seems not superior
Cairncross et al. 2006 (RTOG 9402) Phase III (C) PCV Might have inferior OS (*)
van den Bent et al. 2006 (EORTC 26951) Phase III (C) PCV Inferior PFS

No further treatment. Reported efficacy for RTOG 9402 is based on the 2012 update; while the trial did not meet its primary endpoint, a survival benefit was noted in the population with 1p/19q co-deleted tumors. van den Bent et al. 2013 noted that 1p/19q co-deleted tumors received the more benefit from adjuvant PCV as compared to tumors without 1p/19q co-deletion.

Preceding treatment

  • MRC BR05: Surgery, then RT x 45 Gy or RT x 60 Gy
  • RTOG 9402: Surgery
  • EORTC 26951: Surgery, then RT x 45 Gy with 14.4 Gy boost

References

  1. MRC BR05: Thomas D, Brada M, Stenning S; Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article contains verified protocol PubMed
  2. RTOG 9402: Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006 Jun 20;24(18):2707-14. link to original article contains verified protocol PubMed
    1. Update: Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013 Jan 20;31(3):337-43. Epub 2012 Oct 15. link to original article link to PMC article PubMed
  3. EORTC 26951: van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article contains verified protocol PubMed
    1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed

PCV

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PCV: Procarbazine, CCNU, Vincristine

Variant #1, 60/110/1.4 (capped) x 6

Study Evidence Comparator Efficacy
van den Bent et al. 2006 (EORTC 26951) Phase III (E) No further treatment Superior PFS

van den Bent et al. 2013 noted that 1p/19q co-deleted tumors received the more benefit from adjuvant PCV as compared to tumors without 1p/19q co-deletion. Chemotherapy begins within 4 weeks after completion of radiation therapy:

Preceding treatment

  • Surgery, then RT x 45 Gy with 14.4 Gy boost

Chemotherapy

Supportive medications

42-day cycle for 6 cycles

Variant #2, 60/110/1.4 (no cap)

Study Evidence Comparator Efficacy
Levin et al. 1985 (NCOG 6G61) Phase III (E) BCNU Seems to have superior OS (*)

Note: efficacy is based on the 1990 update; the total number of cycles is not specified in this protocol.

Preceding treatment

  • Surgery, then Hydrea & WBRT

Chemotherapy

6- to 8-week cycles

Variant #3, 60/110/2 x 4

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III (E) 1. RT Seems not superior
2. Temozolomide Seems not superior

Preceding treatment

  • Surgery

Chemotherapy

8-week cycle for 4 cycles

Subsequent treatment

  • Patients with stable disease or better: 2 more cycles of PCV
  • At time of disease progression patients proceeded to receive radiation therapy

Variant #4, 75/130/1.4 (no cap) x 4

Study Evidence Comparator Efficacy
Cairncross et al. 2006 (RTOG 9402) Phase III (E) No chemotherapy Might have superior OS (*)

Reported efficacy is based on the 2012 update; while the trial did not meet its primary endpoint, a survival benefit was noted in the population with 1p/19q co-deleted tumors.

Preceding treatment

  • Surgery

Chemotherapy

6-week cycle for 4 cycles

Subsequent treatment

  • RT x 50.4 Gy + 9 Gy boost

Variant #5, 100/100/1.5 (capped) x 12

Study Evidence Comparator Efficacy
Thomas et al. 2001 (MRC BR05) Phase III (E) No further treatment Seems not superior

Chemotherapy begins 3 to 4 weeks after completion of radiation therapy.

Preceding treatment

  • Surgery, then RT x 45 Gy or RT x 60 Gy

Chemotherapy

Supportive medications

  • Corticosteroid use was left up to physician discretion. It was recommended to not discontinue steroids until at least 6 weeks after radiation therapy. If it was to be discontinued, it should be tapered down gradually over several weeks, or could be titrated down to the lowest tolerated dose.

42-day cycle for up to 12 cycles

References

  1. NCOG 6G61: Levin VA, Wara WM, Davis RL, Vestnys P, Resser KJ, Yatsko K, Nutik S, Gutin PH, Wilson CB. Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas. J Neurosurg. 1985 Aug;63(2):218-23. link to original article contains verified protocol PubMed
    1. Update: Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2):321-4. link to original article PubMed
  2. MRC BR05: Thomas D, Brada M, Stenning S; Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article contains verified protocol PubMed
  3. RTOG 9402: Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006 Jun 20;24(18):2707-14. link to original article contains verified protocol PubMed
    1. Update: Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013 Jan 20;31(3):337-43. Epub 2012 Oct 15. link to original article link to PMC article PubMed
  4. EORTC 26951: van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article contains verified protocol PubMed
    1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed
  5. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
    1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed

Radiation therapy

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Variant #1, 45 Gy

Study Evidence Comparator Efficacy
Bleehen et al. 1991 (MRC BR02) Phase III (C) RT x 60 Gy Inferior OS
Thomas et al. 2001 (MRC BR05) Non-randomized portion of RCT

Radiation therapy starts preferably within 3, but no more than 6, weeks after neurosurgery.

Preceding treatment

  • Surgery

Radiotherapy

One course

Subsequent treatment

Variant #2, 45 Gy with 14.4 Gy boost

Study Evidence
van den Bent et al. 2006 (EORTC 26951) Non-randomized portion of RCT

Radiation therapy starts within 6 weeks after surgery.

Preceding treatment

  • Surgery

Radiotherapy

  • External beam radiotherapy, 1.8 Gy fractions x 25 fractions, given 5 days per week, total dose of 45 Gy to the planning target volume (PTV-1); then a boost of 1.8 Gy fractions x 8 fractions, given 5 days per week, total boost dose of 14.4 Gy to the PTV-2, for a total cumulative dose of 59.4 Gy

One course

Subsequent treatment

Variant #3, 50.4 Gy with 9 Gy boost

Study Evidence
Cairncross et al. 2006 (RTOG 9402) Non-randomized portion of RCT

Radiation therapy starts within 6 weeks after surgery or chemotherapy.

Preceding treatment

Radiotherapy

  • External beam radiotherapy, 1.8 Gy fractions x 28 fractions, given 5 days per week, total dose of 50.4 Gy to the planning target volume (PTV-1); then a boost of 1.8 Gy fractions x 5 fractions, given 5 days per week, total boost dose of 9 Gy to the PTV-2, for a total cumulative dose of 59.4 Gy

One course

Variant #4, 60 Gy

Study Evidence Comparator Efficacy
Bleehen et al. 1991 (MRC BR02) Phase III (E) RT x 45 Gy Superior OS
Thomas et al. 2001 (MRC BR05) Phase III (C) RT, then PCV Seems not superior
van den Bent et al. 2006 (EORTC 26951) Phase III (C) RT, then PCV Inferior PFS
Wick et al. 2009 (NOA-04) Phase III (C) 1. PCV Seems not superior
2. Temozolomide Seems not superior

Preceding treatment

  • Surgery

Radiotherapy

One course

Subsequent treatment

References

  1. MRC BR02: Bleehen NM, Stenning SP; The Medical Research Council Brain Tumour Working Party. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. Br J Cancer. 1991 Oct;64(4):769-74. link to PMC article contains protocol PubMed
  2. MRC BR05: Thomas D, Brada M, Stenning S; Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article contains verified protocol PubMed
  3. RTOG 9402: Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006 Jun 20;24(18):2707-14. link to original article contains verified protocol PubMed
    1. Update: Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013 Jan 20;31(3):337-43. Epub 2012 Oct 15. link to original article link to PMC article PubMed
  4. EORTC 26951: van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article contains verified protocol PubMed
    1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed
  5. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
    1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed
  6. NOA-08: Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. link to original article contains protocol PubMed

RT, then Carmustine

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Regimen

Study Evidence Comparator Efficacy
Shapiro et al. 1989 (BTCG 8001) Phase III (C) 1. Carmustine/Procarbazine & RT Seems not superior
2. Carmustine & Hydrea/Procarbazine & VM-26 & RT Seems not superior

Radiotherapy

  • External beam radiotherapy starting within 3 weeks after surgical resection, with ONE of the following:
    • Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
    • Whole brain & cone down: 172 cGy (rads) fractions x 25 fractions, given over 5 weeks for a total dose of 4300 cGy (4300 rads), then coned-down boost of 172 cGy (rads) fractions x 10 fractions, given over 2 weeks for a dose of 1720 cGy (rads), and a total cumulative dose of 6020 cGy (rads)

One course, followed by:

Chemotherapy

Supportive care

  • Pulmonary function tests (PFTs) checked before start of therapy, and then when cumulative dose of Carmustine (BiCNU) reaches 800 mg/m2 and 1200 mg/m2

8-week cycles, with no more than a maximum cumulative dose of 1500 mg/m2 Carmustine (BiCNU) given

References

  1. BTCG 8001: Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA, Pistenmaa DA. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma: Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989 Jul;71(1):1-9. link to original article contains verified protocol PubMed

RT, then Temozolomide

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Regimen

Study Evidence Comparator Efficacy
van den Bent et al. 2017 (CATNON) Phase III (E) 1. RT
2. Temozolomide & RT
Superior OS
3. Temozolomide & RT, then Temozolomide Not reported

This regimen is meant for patients without 1p/19q loss of heterozygosity (LOH).

Radiotherapy

One course, followed in 4 weeks by:

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 150 mg/m2 PO once per day on days 1 to 5, on empty stomach
    • Cycles 2 to 12: 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycle for 12 cycles

References

  1. CATNON: van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. Epub 2017 Aug 8. link to original article contains verified protocol link to PMC article PubMed

Temozolomide monotherapy

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Variant #1, dose-dense

Study Evidence Comparator Efficacy
Wick et al. 2012 (NOA-08) Phase III (E) Radiation therapy Seems to have non-inferior OS

Chemotherapy

14-day cycles

Variant #2

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III (E) 1. PCV Seems not superior
2. Radiation therapy Seems not superior

Chemotherapy

28-day cycle for 8 cycles

Subsequent treatment

  • SD or better: 4 more cycles of temozolomide. At time of disease progression patients proceeded to receive radiation therapy

Variant #3

Study Evidence
Mikkelsen et al. 2009 Non-randomized

This regimen is meant for patients with 1p/19q loss of heterozygosity (LOH).

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycles 1 & 2: 150 mg/m2 PO once per day on days 1 to 5, on empty stomach
    • Cycle 3 onwards (if no myelosuppression): 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycles

Variant #4

Study Evidence
Taliansky-Aronov et al. 2006 Non-randomized

Chemotherapy

Supportive medications

  • Corticosteroids could be continued at same dose or reduced, but not increased while on study

28-day cycles, given until progression of disease or, in patients with stable disease, up to 24 months

References

  1. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol. 2006 Sep;79(2):153-7. Epub 2006 Jul 20. link to original article contains verified protocol PubMed
  2. Mikkelsen T, Doyle T, Anderson J, Margolis J, Paleologos N, Gutierrez J, Croteau D, Hasselbach L, Avedissian R, Schultz L. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009 Mar;92(1):57-63. Epub 2008 Nov 15. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
    1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed
  4. NOA-08: Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. link to original article contains protocol PubMed

Temozolomide, then Temozolomide & RT, then Temozolomide

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Regimen

Study Evidence
Mikkelsen et al. 2009 Non-randomized

This regimen is meant for patients without 1p/19q loss of heterozygosity (LOH).

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycles 1 & 2: 150 mg/m2 PO once per day on days 1 to 5, on empty stomach
    • Cycle 3 onwards (if no myelosuppression): 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycle for 2 to 4 cycles, followed by:

Chemoradiotherapy

One course, followed by:

Chemotherapy

28-day cycles

References

  1. Mikkelsen T, Doyle T, Anderson J, Margolis J, Paleologos N, Gutierrez J, Croteau D, Hasselbach L, Avedissian R, Schultz L. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009 Mar;92(1):57-63. Epub 2008 Nov 15. link to original article contains verified protocol PubMed content property of HemOnc.org

Temozolomide & RT

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Regimen

Study Evidence Comparator Efficacy
van den Bent et al. 2017 (CATNON) Phase III (E) 1. RT Not reported
2. Temozolomide & RT, then Temozolomide
3. RT, then Temozolomide
Inferior OS

This regimen is meant for patients without 1p/19q loss of heterozygosity (LOH).

Chemoradiotherapy

One course

References

  1. CATNON: van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. Epub 2017 Aug 8. link to original article contains verified protocol link to PMC article PubMed

Temozolomide & RT, then Temozolomide

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Variant #1

Study Evidence Comparator Efficacy
Chang et al. 2017 (RTOG 9813) Phase III (E) 1. Carmustine & RT
2. Lomustine & RT
Seems not superior

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemoradiotherapy

28-day cycle for 12 cycles

Variant #2

Study Evidence Comparator Efficacy
van den Bent et al. 2017 (CATNON) Phase III (E) 1. RT
2. Temozolomide & RT
Superior OS
3. RT, then Temozolomide Not reported

This regimen is meant for patients without 1p/19q loss of heterozygosity (LOH).

Chemoradiotherapy

One course, followed in 4 weeks by:

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 150 mg/m2 PO once per day on days 1 to 5, on empty stomach
    • Cycles 2 to 12: 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycle for 12 cycles

References

  1. RTOG 9813: Chang S, Zhang P, Cairncross JG, Gilbert MR, Bahary JP, Dolinskas CA, Chakravarti A, Aldape KD, Bell EH, Schiff D, Jaeckle K, Brown PD, Barger GR, Werner-Wasik M, Shih H, Brachman D, Penas-Prado M, Robins HI, Belanger K, Schultz C, Hunter G, Mehta M. Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813. Neuro Oncol. 2017 Feb 1;19(2):252-258. link to original article link to PMC article contains verified protocol PubMed
  2. CATNON: van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. Epub 2017 Aug 8. link to original article contains verified protocol link to PMC article PubMed

Recurrent disease, salvage therapy

Bevacizumab monotherapy

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Regimen

Study Evidence
Chamberlain et al. 2008 Non-randomized

Chemotherapy

Supportive medications

  • Use of steroids allowed for control of neurologic signs and symptoms

14-day cycles

References

  1. Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol. 2009 Feb;91(3):359-67. Epub 2008 Oct 25. J Neurooncol. 2009 Feb;91(3):359-67. Epub 2008 Oct 25. link to original article contains verified protocol PubMed
  2. Retrospective: Chamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer. 2009 Apr 15;115(8):1734-43. link to original article PubMed

Carboplatin & Bevacizumab

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Variant #1

Study Evidence
Thompson et al. 2010 Retrospective

Chemotherapy

28-day cycles

Variant #2

Study Evidence
Norden et al. 2008 Retrospective

Chemotherapy

References

  1. Retrospective: Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article PubMed
  2. Retrospective: Thompson EM, Dosa E, Kraemer DF, Neuwelt EA. Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery. 2010 Jul;67(1):87-93. link to original article link to PMC article PubMed

Cyclophosphamide monotherapy

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Regimen

Study Evidence
Chamberlain et al. 2006 Phase II

Chemotherapy

Supportive medications

28-day cycles

References

  1. Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with cyclophosphamide for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer. 2006 Jan 1;106(1):172-9. link to original article contains verified protocol PubMed

Etoposide monotherapy

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Regimen

Study Evidence
Fulton et al. 1996 Phase II

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol. 1996 Feb;27(2):149-55. link to original article contains verified protocol PubMed

Irinotecan monotherapy

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Variant #1, 125 mg/m2, 4 out of 6 weeks

Study Evidence
Friedman et al. 1999 Phase II

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1, 8, 15, 22
    • If tolerated, dose could be increased to 150 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive medications

  • Steroids at lowest dose necessary
  • Avoid laxatives and magnesium-containing antacids due to potential for diarrhea

42-day (6-week) cycles

Variant #2, 350 mg/m2 q3wk

Study Evidence
Chamberlain et al. 2008 Phase II

Chemotherapy

  • Irinotecan (Camptosar) 350 mg/m2 IV over 2 hours once on day 1
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 600 mg/m2 IV over 2 hours once on day 1

Supportive medications

21-day cycles

Variant #3, 600 mg/m2 q3wk

Study Evidence
Chamberlain et al. 2002 Phase I
Chamberlain et al. 2008 Phase II

Note: this is the dose recommended for patients receiving enzyme-inducing antiepileptic drugs (EIAEDs).

Chemotherapy

Supportive medications

21-day cycles

References

  1. Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999 May;17(5):1516-25. link to original article contains verified protocol PubMed
  2. Phase I: Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas. J Neurooncol. 2002 Sep;59(2):157-63. link to original article contains protocol PubMed
  3. Chamberlain MC, Wei-Tsao DD, Blumenthal DT, Glantz MJ. Salvage chemotherapy with CPT-11 for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer. 2008 May 1;112(9):2038-45. link to original article contains verified protocol PubMed

Irinotecan & Bevacizumab

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Regimen

Study Evidence
Vredenburgh et al. 2007 Phase II

Note: Vredenburgh et al. 2007 described 6-week cycles in which treatment was every 2 weeks and was otherwise identical, so its entry was consolidated with Taillibert et al. 2009.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once on day 1, given first
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 340 mg/m2 IV over 90 minutes once on day 1, given first
  • Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second
    • Infusion time is 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive medications

  • "Appropriate antiemetics"

14-day cycles

References

  1. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007 Feb 15;13(4):1253-9. link to original article contains verified protocol PubMed
  2. Retrospective: Taillibert S, Vincent LA, Granger B, Marie Y, Carpentier C, Guillevin R, Bellanger A, Mokhtari K, Rousseau A, Psimaras D, Dehais C, Sierra del Rio M, Meng Y, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology. 2009 May 5;72(18):1601-6. link to original article PubMed

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Variant #1

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III (E) Temozolomide Seems not superior

Preceding treatment

Chemotherapy

8-week cycles until progression

Subsequent treatment

  • At progression, patients who had not previously received temozolomide proceeded to receive salvage temozolomide

Variant #2

Study Evidence
Levin et al. 1980 Non-randomized

Chemotherapy

42-day cycles

Variant #3, higher doses

Study Evidence
Cairncross et al. 1994 Phase II

Chemotherapy

42-day cycles

References

  1. Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. contains protocol PubMed
  2. Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr, Wainman N, Eisenhauer E; National Cancer Institute of Canada Clinical Trials Group. Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol. 1994 Oct;12(10):2013-21. link to original article contains verified protocol PubMed
  3. Retrospective: Kappelle AC, Postma TJ, Taphoorn MJ, Groeneveld GJ, van den Bent MJ, van Groeningen CJ, Zonnenberg BA, Sneeuw KC, Heimans JJ. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology. 2001 Jan 9;56(1):118-20. link to original article PubMed
  4. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
    1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed

Radiation therapy

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Regimen

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III (C) 1. PCV Seems not superior
2. Temozolomide Seems not superior

Preceding treatment

Radiotherapy

Subsequent treatment

  • At progression: PCV if they had previously received temozolomide or temozolomide if they had previously received PCV

References

  1. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
    1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed

Temozolomide monotherapy

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Variant #1

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III (E) PCV Seems not superior

Preceding treatment

Chemotherapy

28-day cycles until progression

Subsequent treatment

  • At progression, patients who had not previously received PCV proceeded to receive salvage PCV

Variant #2, continuous therapy

Study Evidence
Perry et al. 2008 (RESCUE) Phase II

Patients who undergo conventional temozolomide therapy, have surgery and radiation therapy, and then relapse receive:

Chemotherapy

28-day cycles

Patients with progressive disease are changed to:

Given until progression of disease or unacceptable toxicity

Variant #3, traditional dosing

Study Evidence
Nicholson et al. 2007 Non-randomized

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m2 PO once per day on days 1 to 5

28-day cycle for up to 11 cycles

Variant #4

Study Evidence
Yung et al. 1999 Phase II

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Patients who had never previously received chemotherapy: 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received chemotherapy started with 150 mg/m2 PO once per day on days 1 to 5, which could be increased as tolerated to 200 mg/m2 PO once per day on days 1 to 5

Supportive medications

28-day cycle for up to 2 years

References

  1. Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O'Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA; Temodal Brain Tumor Group. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol. 1999 Sep;17(9):2762-71. link to original article contains verified protocol PubMed
  2. Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer. 2007 Oct 1;110(7):1542-50. link to original article contains verified protocol PubMed
  3. RESCUE: Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer. 2008 Oct 15;113(8):2152-7. link to original article contains verified protocol PubMed
    1. Update: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):2051-7. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
  4. NOA-04: Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
    1. Update: Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. Epub 2016 Jul 1. Erratum in: Neuro Oncol. 2016 Nov;18(11):e1. link to original article link to PMC article PubMed